Protein Structure Prediction Methods.

Most computational protein structure prediction methods are designed for either template based or template-free (ab initio) structure prediction. The approaches that integrate the prediction capabilities of both template-based modeling and template-free modeling are needed to synergistically combine the two kinds of methods to improve protein structure prediction. In this work, we develop a new method to integrate several protein structure prediction methods including our template-based MULTICOM server, our ab initio contact-based protein structure prediction method CONFOLD, our multi-template-based model generation tool MTMG, and locally installed external Rosetta, I-TASSER and RaptorX protein structure prediction tools to improve protein structure prediction of a fullspectrum difficulty ranging from easy, to medium and to hard. Our method participated in the 11(th) community-wide Critical Assessment of Techniques for Protein Structure Prediction (CASP11) in 2014 as MULTICOM-NOVEL server. It was ranked among top 10 methods for protein tertiary structure prediction according to the official CASP11 assessment, which demonstrates that integrating complementary modeling methods is useful for advancing protein structure prediction.

Protein structure prediction is one of the most challenging problems in computational biology. Given a protein's amino acid sequence, a simplified version of the problem is to find an on-lattice self-avoiding walk that minimizes the interaction energy among the amino acids. In this paper, we present a memory-based local search method for the simplified problem using Hydrophobic-Polar energy model and Face Centered Cubic lattice. By memorizing local minima and then avoiding their neighbohood, our approach significantly improves the state-of-the-art local search method for protein structure prediction on a set of standard benchmark proteins.

Protein folding is a central challenge in computational biology, with important applications in molecular biology, drug discovery and catalyst design. As a hard combinatorial optimisation problem, it has been studied as a potential target problem for quantum annealing. Although several experimental implementations have been discussed in the literature, the computational scaling of these approaches has not been elucidated. In this article, we present a numerical study of quantum annealing applied to a large number of small peptide folding problems, aiming to infer useful insights for near-term applications. We present two conclusions: that even naïve quantum annealing, when applied to protein lattice folding, has the potential to outperform classical approaches, and that careful engineering of the Hamiltonians and schedules involved can deliver notable relative improvements for this problem. Overall, our results suggest that quantum algorithms may well offer improvements for problems in the protein folding and structure prediction realm.

Frediction of the three-dimensional structure of a protein from its amino acid sequence can be considered as a global optimization problem. In this paper, the Chaotic Artificial Bee Colony (CABC) algorithm was introduced and applied to 3D protein structure prediction. Based on the 3D off-lattice AB model, the CABC algorithm combines global search and local search of the Artificial Bee Colony (ABC) algorithm with the Chaotic search algorithm to avoid the problem of premature convergence and easily trapping the local optimum solution. The experiments carried out with the popular Fibonacci sequences demonstrate that the proposed algorithm provides an effective and high-performance method for protein structure prediction.

ProteinShop Gives Researchers a Hands-On Tool for Manipulating, Visualizing Protein Structures. The Human Genome Project and other biological research efforts are creating an avalanche of new data about the chemical makeup and genetic codes of living organisms. But in order to make sense of this raw data, researchers need software tools which let them explore and model data in a more intuitive fashion. With this in mind, researchers at Lawrence Berkeley National Laboratory and the University of California, Davis, have developed ProteinShop, a visualization and modeling program which allows researchers to manipulate protein structures with pinpoint control, guided in large part by their own biological and experimental instincts. Biologists have spent the last half century trying to unravel the ''protein folding problem,'' which refers to the way chains of amino acids physically fold themselves into three-dimensional proteins. This final shape, which resembles a crumpled ribbon or piece of origami, is what determines how the protein functions and translates genetic information. Understanding and modeling this geometrically complex formation is no easy matter. ProteinShop takes a given sequence of amino acids and uses visualization guides to help generate predictions about the secondary structures, identifying alpha helices and flat beta strands, and the coil regions that bind them. Once secondary structures are in place, researchers can twist and turn these pre-configurations until they come up with a number of possible tertiary structure conformations. In turn, these are fed into a computationally intensive optimization procedure that tries to find the final, three-dimensional protein structure. Most importantly, ProteinShop allows users to add human knowledge and intuition to the protein structure prediction process, thus bypassing bad configurations that would otherwise be fruitless for optimization. This saves compute cycles and accelerates the entire process, so that more and larger problems can be attempted. Currently, the program designers are working to make ProteinShop more applicable and adaptable to different protein folding methodologies. If users could manipulate structures from a biological point of view, and then put them back in the queue for more optimization, the process of experimentation and discovery in protein research could be greatly enhanced. The group is also investigating the use of stereoscopic rendering and three-dimensional input devices to remove the limitations of a two-dimensional interface. Clearly, protein-folding research will have far-reaching ramifications. It could lead to new insights about diseases ranging from Alzheimer's to Cystic fibrosis, which scientists believe are caused by protein folding gone wrong. A better understanding of protein structures could also lead to the engineering of altogether new proteins, and shed light on how drugs bind proteins to alter their structure and function. Above all, ProteinShop is an important tool that will help scientists unravel one of the most challenging problems that theoretical and computational chemistry has to offer.

Artificial intelligence (AI) has grown widely into diverse areas of research over the last decade. Publications distributed over the years disclose that biochemistry and analytical chemistry are incorporating AI to the utmost level. Enormous complex data sets are produced by analytical instruments comprising a treasure of information which is very helpful to analytical chemists in characterization. Despite this, we lack capabilities in data analysis and algorithms, which restricts our aptitude to discover and employ this data entirely. Machine learning and AI are being instigated to deal with this current challenge by accelerating several other applications in analytical chemistry. A critical valuation of illustrative reports amalgamating AI with analytical chemistry, spectroscopies, and several sensors has been discussed widely. This comprehensive review evaluates the AI advancement in data interpretation, the assistance of AI in analyte identification and quantification in proteomics and metabolomics, AI databases for primary and secondary metabolites information, regulatory and ethical guidelines in analytical chemistry incorporating AI, machine learning applications in drug discovery, agriculture, cosmetic, and food and separation techniques. In summary, this current review puts forward a thorough examination concerning the advancements of AI in different domains of chemistry and strives to facilitate comprehension of its forthcoming trajectories.

Background: Recent progress in protein structure prediction by AlphaFold has opened new avenues to decipher biological functions from the perspective of structural biology based on the proteomics level. Methods: To meet these challenges, in this perspective, three scales of networks for protein structures, including structural protein-protein networks, protein structural networks, and elastic network models were introduced for high-throughput modeling of protein functional sites and protein dynamics. Conclusion: In the post-AlphaFold era, it is assumed that the integration of biomolecular networks may be leveraged in the future to develop a modeling framework that addresses protein structure-based functions with the application in drug discovery.

In recent years, machine learning models have shown substantial progress in predicting molecular properties. However, integrating molecular graph structures with sequence information continues to present a significant challenge. In this paper, we introduce Multi-MoleScale, a novel multi-scale framework designed to address this challenge. By combining Graph Contrastive Learning (GCL) with sequence-based models like BERT, Multi-MoleScale enhances the prediction of molecular properties by capturing both structural and contextual representations of molecules. Specifically, the model leverages GCL to effectively capture the intrinsic graph-based features of molecules while utilizing BERT’s pretraining capabilities to learn the contextual relationships within molecular sequences. The contrastive learning component enables Multi-MoleScale to distinguish between relevant and irrelevant molecular features, thereby enhancing its predictive accuracy across diverse molecular types. To assess the performance of our method, we conducted experiments on several widely used public datasets, including 12 molecular property datasets, the ADMET dataset, and 14 breast cancer cell line datasets. The results show that Multi-MoleScale consistently outperforms existing deep learning and self-supervised learning approaches. Notably, the model does not require handcrafted features, making it highly adaptable and versatile for a variety of molecular discovery tasks. This makes Multi-MoleScale a promising tool for applications in drug discovery, materials science, and other molecular research fields. Our data and code are available at https://github.com/pdssunny/Multi-MoleScale. Supplementary InformationThe online version contains supplementary material available at 10.1186/s13321-025-01126-w.

Proteins are one of the essential bio-molecules and control almost all functions in the living cell. They act to perform many of the biological functions in different forms, including catalytic activities in the cell (enzymes), transport proteins (hemoglobin), transmission and coordination between cells and organs of the body (hormones), molecules of the immune system (antibodies), and the transport of small molecules across the cell membranes and so on. Since the origin of life, the protein molecules have attained a specifically designed architecture by nature under the normal physiological conditions. Different functional proteins adopt compact three-dimensional shapes that are biologically active, known as the native conformations. Similarly, if any of the physiological conditions deviate, then the protein extends its conformation. The protein folding problem describes how the native conformation is predicted from a given amino acid sequence. The study of protein folding mechanisms has attracted researchers to conduct intensive research both in experimental and theoretical approaches over the past few years due to its tremendous scope and industrial applications. It is very straightforward to analyze the amino acid sequence of a given protein; however, the prediction of the three-dimensional structure followed by its folding mechanism is a challenging task. For almost 50 years, researchers have been trying to study the protein folding problem using many computational approaches. Many of the artificial intelligence algorithms are suitably used to study the protein folding mechanism. There is a broader scope in applying artificial neural networks (ANN) to study protein folding. As per the recent literature, ANN-based protein folding algorithms are a million times faster than any other algorithms. So in this chapter, the details of ANN-based algorithms and their implementation in the study of protein folding has been discussed by narrating the recent literature.

We discuss recent advancements in structural biology methods for investigating sites of protein-protein interactions. We will inform readers outside the field of structural biology about techniques beyond crystallography, and how these different technologies can be utilized for drug development. Advancements in cryo-electron microscopy (cryoEM) and micro-electron diffraction (microED) may change how we view atomic resolution structural biology, such that well-ordered macrocrystals of protein complexes are not required for interface identification. However, some drug discovery applications, such as lead peptide compound generation, may not require atomic resolution; mass spectrometry techniques can provide an expedited path to generation of lead compounds. New crosslinking compounds, more user-friendly data analysis, and novel protocols such as protein painting can advance drug discovery programs, even in the absence of atomic resolution structural data. Finally, artificial intelligence and machine learning methods, while never truly replacing experimental methods, may provide rational ways to stratify potential druggable regions identified with mass spectrometry into higher and lower priority candidates. Electron diffraction of nanocrystals combines the benefits of both x-ray diffraction and cryoEM, and may prove to be the next generation of atomic resolution protein-protein interface identification. However, in situations such as peptide drug discovery, mass spectrometry techniques supported by advancements in computational methods will likely prove sufficient to support drug discovery efforts. In addition, these methods can be significantly faster than any crystallographic or cryoEM methods for identification of interacting regions.

Protein structure prediction aims to model the three‐dimensional (3D) structure of so far structurally uncharacterised proteins from their amino acid sequence. Motivated by the observation that homologous proteins with related amino acid sequences have similar 3D structures, protein homology modelling uses comparative methods to generate models for a target protein based on one or more related proteins with known 3D structure. The coordinates of the model are generated based on alignments between the target's and template's amino acid sequences, which define the correspondence between residues in both proteins. Ultimately, the quality of a computational model determines its usefulness for specific biomedical applications. Therefore, model quality estimation methods are used to identify unreliable or erroneous regions in the resulting models, and to estimate the overall accuracy of a model. Homology modelling (or comparative modelling) is currently the most accurate computational method available to routinely generate models of sufficient quality for various applications in life science research. Comparative protein modelling methods have been completely automated in recent years, and several Internet servers offer protein modelling services which are reliable and easy to use – also for the nonexpert in computational biology. Key Concepts: Protein structure prediction aims to model the three‐dimensional structure of so far structurally uncharacterised proteins (‘target’) based on their amino acid sequence. Homologous proteins with related amino acid sequences have similar three‐dimensional structures. Protein homology modelling uses information from one or more related proteins with known three‐dimensional structure (‘template’) to generate models for the target protein. Sensitive sequence searching methods are applied to identify template proteins with known structures in large databases. An alignment between the target's and template's amino acid sequences describes the correspondence between residues in both proteins. The coordinates of the model are constructed by extracting positional information from the corresponding structural template. Segments of the target protein not covered by template information (e.g. insertions/deletion in the alignment) have to be constructed using de novo modelling methods. Model quality estimation methods are used to identify unreliable or erroneous regions in the resulting models. Ultimately, the quality of a structural model determines its usefulness for specific biomedical applications.

Proteins are essential parts of our life and participate in virtually every process within a cell. The understanding of protein structures is vital to determine the function of a protein. Protein structure prediction (PSP) from amino acid sequence is one of the high focus problems in bioinformatics today. This is due to the fact that the biological function of the protein is determined by its three dimensional structure. Thus, protein structure prediction is a fundamental area of computational biology. Its importance is intensed by large amounts of sequence data coming from PDB (Protein Data Bank) and the fact that experimentally methods such as X-ray crystallography or Nuclear Magnetic Resonance (NMR)which are used to determining protein structures remains very expensive and time consuming. For minimizing the time, computational methods are used for protein folding and structure prediction problem. In this paper results of protein p53 are discussed.

Molecular docking is a key tool in structural biology and computer-assisted drug design. Molecular docking is a method which predicts the preferred orientation of a ligand when bound in an active site to form a stable complex. It is the most common method used as a structure-based drug design. Here, the authors intend to discuss the various types of docking methods and their development and applications in modern drug discovery. The important basic theories such as sampling algorithm and scoring functions have been discussed briefly. The performances of the different available docking software have also been discussed. This chapter also includes some application examples of docking studies in modern drug discovery such as targeted drug delivery using carbon nanotubes, docking of nucleic acids to find the binding modes and a comparative study between high-throughput screening and structure-based virtual screening.

Computationally generated models of protein structures bridge the gap between the practically negligible price tag of sequencing and the high cost of experimental structure determination. By providing a low-cost (and often free) partial alternative to experimentally determined structures, these models help biologists design and interpret their experiments. Obviously, the more accurate the models the more useful they are. However, methods for protein structure prediction generate many structural models of various qualities, necessitating means for the estimation of their accuracy. In this work we present MESHI_consensus, a new method for the estimation of model accuracy. The method uses a tree-based regressor and a set of structural, target-based, and consensus-based features. The new method achieved high performance in the EMA (Estimation of Model Accuracy) track of the recent CASP14 community-wide experiment (https://predictioncenter.org/casp14/index.cgi). The tertiary structure prediction track of that experiment revealed an unprecedented leap in prediction performance by a single prediction group/method, namely AlphaFold2. This achievement would inevitably have a profound impact on the field of protein structure prediction, including the accuracy estimation sub-task. We conclude this manuscript with some speculations regarding the future role of accuracy estimation in a new era of accurate protein structure prediction.

AIMOES: Archive information assisted multi-objective evolutionary strategy for ab initio protein structure prediction